Characterizing new redox roles for protein ubiquitination in human cells

点击翻译按钮获取中文摘要

PROJECT SUMMARY Human cells are constantly subjected to oxidative stress due to the exposure to solar UV radiation and to pollutants in the water and in the atmosphere. To cope with the harms of oxidative stress that can lead to cellular malfunction and death, cells must reprogram gene expression and adjust the dynamics of protein production and degradation. Ubiquitin is a prominent protein modifier that controls the fate and the function of numerous proteins, and reshapes the proteome during environmental stresses. In response to oxidative stress, thousands of proteins accumulate ubiquitin modification and are involved in a variety of functions that support cellular survival. My lab discovered a new ubiquitin-dependent pathway that regulates protein production in yeast; however little is known about the importance and regulation of this pathway in human cells. In addition, to modify a large number of proteins with ubiquitin, human cells rely on hundreds of ubiquitin enzymes that selectively recognize their dedicated targets. However, the contribution of each ubiquitin enzyme to cellular resistance to stress is largely unknown. The purpose of the proposed project is to identify and characterize the roles of ubiquitin as a master regulator of the stress response. In Aim 1, we will investigate the molecular details of localized ubiquitin accumulation under oxidative stress, including when, why, and how it occurs. In Aim 2, we will investigate different aspects of cellular response to stress using genome editing methodologies targeting functional domains of > 700 ubiquitin enzymes. As oxidative stress is the underlying cause of a variety of human conditions such as aging, tumor progression, and degenerative disease, our research will provide a new understanding of ubiquitin function in the promotion of cellular health. Defining the importance of these pathways and the physiological role of ubiquitin enzymes will provide several avenues for drug development and it will allow us to learn the fundamental principles of the enzymatic regulation of protein ubiquitination during cellular resistance to stress.